• E-mail
• Print
• Comment
• Font Size
• Digg
• del.icio.us
• Discuss article

CDX2 Is a Useful Marker of Intestinal-Type Differentiation: A Tissue Microarray-Based Study of 629 Tumors From Various Sites

Posted on: Thursday, 8 September 2005, 03:00 CDT

Context.-CDX2, a critical nuclear transcription factor for intestinal development, is expressed in intestinal epithelium and adenocarcinomas.

Objectives.-To determine if CDX2 is a useful marker for intestinal-type differentiation and to correlate tumor histology with CDX2 staining in colorectal adenocarcinomas.

Design.-Tissue microarrays from 71 colorectal adenocarcinomas, 31 hepatocellular carcinomas, 47 lung adenocarcinomas, 55 squamous cell carcinomas of the lung, 69 neuroendocrine carcinomas of the lung and 43 of the pancreas, 57 pancreatic adenocarcinomas, and 256 endometrial adenocarcinomas were stained with antibody against CDX2.

Results.-CDX2 staining was positive in 51 (71.8%) of 71 colorectal cancers, including 38 (74.5%) of 51 well- or moderately differentiated tumors and 13 (65.0%) of 20 high-grade tumors. Of the high-grade tumors, 5 (71.4%) of 7 mucinous, 3 (100%) of 3 signet ring cell, and 5 (50.0%) of 10 poorly differentiated tumors were positive. Other tumors showing occasional CDX2 staining included 1 of 30 well- or moderately differentiated neuroendocrine carcinomas of the lung and 2 of 43 from the pancreas, 1 of 47 lung adenocarcinomas, 3 of 57 pancreatic adenocarcinomas, and 15 of 256 endometrial carcinomas. Hepatocellular, poorly differentiated neuroendocrine carcinoma of the lung and squamous cell carcinomas of the lung were not immunoreactive for CDX2.

Conclusions.-CDX2 is a useful marker for intestinal-type differentiation, is rarely seen in tumors from the other sites evaluated, and may be useful in determining the site of origin for some metastatic tumors. However, CDX2 is not a sensitive marker for poorly differentiated colorectal carcinoma.

(Arch Pathol Lab Med. 2005;129:1100-1105)

CDX2 is an intestine-specific nuclear transcription factor encoded by the human homologue of the homeobox gene, Drosophila caudal.1 Studies have demonstrated the critical role of the CDX2 gene in early embryologie development through adulthood. Its expression at multiple sites during embryogenesis is responsible for its influence in anteroposterior patterning,2 in addition to its better known role in intestinal tract development and establishment of intestinal cell phenotype.3-5 In adult tissues, however, CDX2 protein expression is restricted to the nuclei of epithelial cells lining the villi and crypts in the small and large intestines, with decreasing expression in the distal portion of the rectum.6-8 It has been shown to regulate expression of intestine-specific enzymes in mature intestinal tissue9^11 and may play an important role in cell differentiation and proliferation.12,13

Owing to the essential role of CDX2 in intestinal development and cell phenotype, it has been the focus of numerous studies concerning colorectal tumorigenesis. Models using knockout mice have shown that loss of Cdx2 might be important for the development of colorectal tumors. While total loss of Cdx2 has proven lethal during embryogenesis,14 Cdx2 heterozygotes treated with a DNA mutagen, azomethane, developed more invasive adenocarcinomas in the distal colon when compared with wildtype mice.15 Another study evaluated compound mutant mice with lesions in the Ape gene and Cdx2 heterozygosity.16 Ape lesions alone led to an increased number of adenomas in the small intestine only. However, decreased protein expression from both genes correlated with increased development of adenomatous polyps in the distal colon. These murine studies suggest a possible tumor suppressor role for Cdx2 in the large intestine, where loss of expression may play a pivotal role in the development and progression of colorectal cancer.

While some human colon cancer cell lines have also demonstrated reduced expression of CDX2, providing a possible explanation for colorectal tumorigenesis,17 it appears that few human colorectal tumors actually exhibit mutations or loss of expression of either CDX2 allele.18-21 Some exceptions include colorectal tumors with microsatellite instability, in which mismatch repair defects lead directly to mutations in the CDX2 gene22,23 and poorly differentiated or high-grade colorectal tumors.23-25 A defect in CDX2 transcription rather than gene mutation (except in microsatellite unstable tumors) is the suggested mechanism by which diminished or absent CDX2 expression occurs in a minority of human colorectal carcinomas.21 However, site-specific expression of CDX2 in normal intestines and expression in most intestinal adenocartinomas are preserved, making CDX2 protein a potentially useful marker for both primary and metastatic intestinal adenocarcinomas.

Table 1. Comparison of CDX2 Staining in Tumors From Various Sites

Table 2. Comparison of CDX2 Staining in Colorectal Carcinomas of Different Histologie Subtypes

Recent studies examining the immunohistochemical expression of CDX2 in tumors from various sites suggest that it is specific for intestinal adenocarcinomas.25-28 It has been suggested that poorly differentiated colorectal carcinomas do not express CDX2, but this opinion remains controversial.23-25 Using tissue microarrays and a monoclonal antibody against CDX2, we demonstrate that CDX2 is a useful marker for intestinal-type differentiation in neoplastic epithelium by comparing tumors of various sites while expanding the quantity and types of tumors evaluated for CDX2 staining. Further correlation between tumor histology and CDX2 immunoreactivity was also assessed in colorectal adenocarcinomas to confirm the loss of CDX2 expression in poorly differentiated colorectal carcinomas.

MATERIALS AND METHODS

Formalin-fixed, paraffin-embedded tissue blocks from 629 previously characterized, primary malignant neoplasms were obtained from the archival files of the Department of Pathology, The Ohio State University Medical Center, Columbus. These cases included 71 colorectal adenocarcinomas, 31 hepatocellular carcinomas, 69 neuroendocrine carcinomas of the lung (30 well or moderately differentiated and 39 poorly differentiated), 47 adenocarcinomas of the lung, 55 squamous cell carcinomas of the lung, 43 neuroendocrine carcinomas of the pancreas (well or moderately differentiated), 57 pancreatic adenocarcinomas, and 256 endometrial carcinomas.

Twenty tissue microarrays were previously made with between 16 and 400 cores. For each tumor type, a tissue core diameter of either 0.6, 1.5, or 2.0 mm was used. Tissue cores from formalin-fixed, paraffin-embedded blocks were arrayed using a manual device (Beecher Instruments, Silver Springs, Md). For the 0.6-mm cores, 2 to 4 cores were taken from each tissue block and inserted into new paraffin blocks. The other arrays were made using 2 cores from each tissue block. The arrayed tissue was cut at 4 m and placed on positively charged slides.

Immunohistochemical staining was performed on the arrayed tissue. Slides were placed in a 60C oven for 1 hour, cooled, and deparaffinized and rehydrated through xylenes and graded ethanol solutions to water. All slides were quenched for 5 minutes in a 3% hydrogen peroxide solution in water to block for endogenous peroxidase. Antigen retrieval was performed by a heat method in which the specimens were placed in a citric acid solution (Target Retrieval Solution, pH 6.1; DakoCytomation, Carpinteria, Calif) for 25 minutes at 94C using a vegetable steamer. Slides were then placed in a Dako Autostainer immunostaining system for use with immunohistochemistry and incubated for 60 minutes with CDX2 monoclonal antibody (clone CDX2-88, 1:50; BioGenex, San Ramon, Calif). The antibody detection system used was the EnVision+ Dual Link, a labeled polymer system (DakoCytomation). Staining was visualized using 3,3'-diaminobenzidine chromogen. Slides were then counterstained in Richard Alien hematoxylin, dehydrated through graded ethanol solutions, and cover-slipped.

The slides were reviewed by 2 pathologists (L.B.D. and W.L.F.), and positivity was defined as greater than 5% nuclear staining in either core after staining. The positive control was normal colon and it stained appropriately. Additionally, the grade and histologie type of colorectal adenocarcinomas were determined according to criteria of the World Health Organization Classification of Tumours.29 Well- and moderately differentiated tumors were grouped together as low-grade tumors and were compared with high-grade tumors, which included poorly differentiated tumors, mucinous carcinomas, and signet ring cell carcinomas.

RESULTS

Normal colon demonstrated strong nuclear staining. Table 1 shows all CDX2 immunohistochemical staining results for the various tumors. Nuclear staining for CDX2 was present in 51 (71.8%) of 71 colorectal cancers. When CDX2 expression in colorectal cancers was examined in low-grade versus high-grade tumors, 38 (74.5%) of 51 well- or moderately differentiated tumors and 13 (65.0%) of 20 high- grade tumors were positive (Table 2). Of the high-grade carcinomas, 5 (71.4%) of 7 of the mucinous and 3 (100%) of 3 of the signet ring cell carcinomas were positive for CDX2 expression. In the remaining poorly differentiated carcinomas, 5 (50.0%) of 10 were positive for CDX2 expression. Figure 1 (A through D) shows the CDX2 staining patterns among representative sections of histologie sub\types of colorectal cancers.

Figure 1. CDX2 staining in colorectal carcinomas. A, Well- differentiated adenocarcinoma with positive staining (original magnification 40). B, Poorly differentiated adenocarcinoma with positive staining (original magnification 40). C, Mucinous adenocarcinoma with positive staining (original magnification 40). D, Signet ring cell adenocarcinoma with positive staining (original magnification 40).

Rare tumors from other sites were also immunoreactive for CDX2. Of the other tumors staining for CDX2,1 (3.3%) of 30 was a well- or moderately differentiated neuroendocrine carcinoma of the lung, 2 (4.7%) of 43 were wellor moderately differentiated neuroendocrine carcinomas of the pancreas (Figure 2, A), 1 (2.1%) of 47 was a moderately differentiated adenocarcinoma of the lung, 3 (5.3%, including 1 intraductal papillary mucinous carcinoma) of 57 were pancreatic adenocarcinomas, and 15 (5.9%) of 256 were endometrial carcinomas (Figure 2, B). No hepatocellular carcinoma (Figure 2, C), poorly differentiated neuroendocrine carcinoma of the lung, or squamous cell carcinoma of the lung (Figure 2, D) showed staining for CDX2.

COMMENT

The homeobox gene family encodes for nuclear transcription factors that control and regulate vital cell processes during embryologie development. Body segmentation and tissue patterning in Drosophila melanogaster are controlled by the classic homeobox gene, caudal.30 Mammalian homologues of caudal have been identified in mice (Cdxl, Cdx2, and Cdx4)31-33 and in humans (CDXl and CDX2).1-34 Experimental murine models have demonstrated that the nuclear transcription factor CDX2 is critical in gut development, establishing and maintaining an intestinal cell phenotype, regulation of cell proliferation, and activation of genes that produce intestine-specific factors. In human tissue, nuclear CDX2 protein has been demonstrated by immunohistochemistry in epithelium of the small and large intestine as expected, but has also been shown in appendiceal epithelium, pancreatic ductal cells, and pancreatic centroacinar cells.26,28

The regulatory role of CDX2 in intestinal tract development and cell phenotype suggests that CDX2 may be a useful immunohistochemical marker for intestinal-type differentiation in metaplastic and neoplastic tissues. Immunoreactivity for CDX2 has been shown previously in chronic atrophie gastritis,35 the goblet and columnar cells of intestinal metaplasia in Barrett esophagus,36,37 and in intraductal papillary mucinous neoplasms of the pancreas with intestinal-type epithelium.38 Primary adenocarcinomas of sinonasal,39 lung,40,41 gastroesophageal,25-27 pancreaticobiliary,25-28,42 and ovarian43 origin also demonstrate variable CDX2 staining. Our study confirmed these findings in pancreatic and lung adenocarcinomas, which showed uncommon staining in 5.3% and 2.1% of tumors, respectively. We also collected the largest group of arrayed endometrial adenocarcinomas for CDX2 evaluation to date and observed infrequent staining (5.8%) among these tumors as well. However, the highest frequency of CDX2 staining occurred in colorectal carcinomas (71.8%) when compared with tumors from other sites. Our findings support previous studies that found the majority of all colorectal carcinomas stained with antibody against CDX2.25-28. Therefore, the high frequency of CDX2 staining in colorectal adenocarcinomas, staining in extraintestinal tumors with intestinal-type epithelium, and uncommon staining in tumors from various sites lacking an intestinal phenotype suggests it is a useful marker for intestinal-type differentiation.

Figure 2. CDX2 staining in tumors from various sites. A, Well- differentiated neuroendocrine carcinoma of the pancreas with positive staining (original magnification 40). B, Endometrial adenocarcinoma with positive staining (original magnification 40). C, Hepatocellular carcinoma with negative staining (original magnification 40). D, Squamous cell carcinoma of the lung with negative staining (original magnification 40).

Among colorectal adenocarcinomas, the relationship between tumor grade and CDX2 staining has been controversial. An earlier study reported that there did not seem to be any correlation between tumor grade and the percentage of cells staining, in spite of some high- grade adenocarcinomas that showed fewer immunoreactive cells.27 A more recent study noted that poorly differentiated tumors had a lower frequency of CDX2 staining compared to the remaining lower- grade colorectal carcinomas.25 We observed that the high-grade tumors showed a lower frequency of CDX2 staining (65%) versus the low-grade, well- or moderately differentiated tumors (74.5%). Our data support the contention that high-grade colorectal adenocarcinomas demonstrate a lower frequency of CDX2 staining than lower-grade tumors.

Further study of high-grade colorectal carcinomas revealed that not all histologie subtypes of high-grade tumors exhibit loss of CDX2 expression. We found that mucinous and signet ring cell carcinomas, considered high grade by convention, showed a frequency of tumor staining (71.4% and 100%, respectively) that was comparable to the well- or moderately differentiated tumors (75%). Mucinous and signet ring cell tumors maintain many characteristics of intestinal epithelium, such as abundant mucin production. seemingly, these tumors would express CDX2. Of the remaining high-grade carcinomas, 10 poorly differentiated tumors showed staining in only 50% of tumors. These findings corroborate studies with colon cancer cells,17 colon tumors from rats,24 and human colorectal carcinomas23,24; each of these studies demonstrated decreased CDX2 expression in poorly or undifferentiated tumors. While it initially appeared that high-grade colorectal carcinomas showed decreased CDX2 staining when compared to low-grade tumors, further analysis of staining among histologie subtypes of high-grade tumors revealed that the decrease in tumor staining observed in these tumors is likely a reflection of tumor histology and not tumor grade alone. Our data suggest that despite tumor grade, CDX2 is a useful stain for mucinous and signet ring cell carcinomas of the colon, in addition to lower-grade, well- or moderately differentiated colorectal cancers. CDX2 does not appear to be a sensitive marker for poorly differentiated colorectal carcinomas and may be an unreliable marker of poorly differentiated colorectal tumor metastases. Whether this subset of tumors actually exhibits clinicopathologic features and biologic behavior that is different from other poorly differentiated tumors has yet to be determined.

CDX2 staining was also seen in a minority of well- or moderately differentiated neuroendocrine carcinomas of the lung and pancreas, sites at which CDX2 expression does not appear to be important for normal development. CDX2 staining has been demonstrated previously in gastrointestinal carcinoids, with a differential staining frequency based on location along the gastrointestinal tract.26,27,44-46 Therefore, some studies have proposed the use of CDX2 to stain metastatic gastrointestinal neuroendocrine tumors, since morphology is indistinguishable in neuroendocrine tumors from various sites. Others have cautioned that CDX2 expression can be found in extraintestinal neuroendocrine tumors as well, specifically well-differentiated neuroendocrine tumors of the pancreas and high- grade neuroendocrine carcinomas from numerous organs.44 While none of the poorly differentiated neuroendocrine carcinomas of the lung were positive for CDX2 in our study, we confirmed that well- or moderately differentiated neuroendocrine carcinomas of extraintestinal sites, such as the lung and pancreas, stained for CDX2 (2.1% and 4.7%, respectively), although infrequently. These findings may further limit the diagnostic usefulness of this stain for determining the site of origin for a metastatic neuroendocrine carcinoma.

In conclusion, CDX2 is a useful marker of intestinaltype differentiation. By expanding the numbers and types of tumors evaluated for CDX2 expression, we have confirmed that CDX2 may be useful in determining the site of origin for some metastatic intestinal-type tumors. It is clear, however, that when CDX2 is used to stain colorectal tumors, histology may affect its sensitivity, rendering it less useful in determining site of origin for some metastatic tumors. Among colorectal cancers, CDX2 was a relatively sensitive marker of intestinal origin in the well-differentiated, moderately differentiated, mucinous, and signet ring cell carcinomas. CDX2 may be less useful in poorly differentiated metastatic colorectal cancers. Furthermore, expression of CDX2 is rarely seen in extraintestinal adenocarcinomas and neuroendocrine carcinomas. Therefore, CDX2, like any immunohistochemical stain, is best used within the context of a panel of other markers after careful review of the histologie features of the tumor.

References

1. Drummond F, Putt W, Fox M, Edwards YH. Cloning and chromosome assignment of the human CDX2 gene. Ann Hum Genet. 1997;61 393-400.

2. Chawengsaksophak K, de CraaffW, Rossant J, Deschamps J, Beck F. Cdx2 is essential for axial elongation in mouse development. Proc Nat! Acad Sd USA. 2004;101:764l-7645.

3. Mutoh H, Hakamata Y, Sato K, et al. Conversion of gastric mucosa to intestinal metaplasia in Cdx2-expressing transgenic mice. Biochem Biophys Res Commun. 2002;294:470-479.

4. Beck F, Chawengsaksophak K, Waring P, Playford RJ, Furness JB. Reprogramming of intestinal differentiation and intercalary regeneration in Cdx2 mutant mice. Proc Natl Acad Sd U S A. 1999;96:7318-7323.

5. Silberg DG, Sullivan J, Kang E, et al. Cdx2 ectopic expression induces gastric intestinal metaplasia in transgenic mice. Gastroenterology. 2002;122:689-696.

6. Silberg DG, Swain GP, Suh ER, Traber PG. Cdx1 and Cdx2 expression during intestinal development. Gastroenterology. 20\10;119:961-971.

7. James R, Erler T, Kazenwadel J. Structure of the murine homeobox gene cdx-2: expression in embryonic and adult intestinal epithelium. J Biot Chem. 1994)269:15229-15237.

8. MaIIo GV, Rechreche H, Frigcrio JM, et al. Molecular cloning, sequencing and expression of the mRNA encoding human Cdx1 and Cdx2 homeobox: downregulation of Cdxl and Cdx2 mRNA expression during colorectal carcinogenesis. IntJ Cancer. 1997;74:35-44.

9. Troelsen JT, Mitchelmore C, Spodsberg N, Jensen AM, Noren O, Sjostrom H. Regulation of lactase-phlorizin hydrolase gene expression by the caudal-related homeodomain protein Cdx-2. Biochem J. 1997;322(pt 31:833-838.

10. Fang R, Santiago NA, Olds LC, Sibley E. The homeodomain protein Cdx2 regulates lactase gene promoter activity during enterocyte differentiation. Gastroenterology. 2000;118:115-127.

11. Boudreau F, Rings EH, van Wering HM, et al. Hepatocyte nuclear factor-1 alpha, GATA-4, and caudal related homeodomain protein Cdx2 interact functionally to modulate intestinal gene transcription: implication for the developmental regulation of the sucrase-isomaltase gene. I Biol Chem. 2002;277:31909-31917.

12. Lynch JP, Silberg DG. To differentiate or proliferate? The interaction between PI3K/PTEN and Cdx2. Gastmenterology. 2002;123:1395-1397.

13. Suh E, Traber PG. An intestine-specific homeobox gene regulates proliferation and differentiation. MoI Cell Biol. 1996;1 6:619-625.

14. Chawengsaksophak K, James R, Hammond VE, Kontgen F, Beck F. Homeosis and intestinal tumours in Cdx2 mutant mice. Nature. 1997;386:84-87.

15. Bonhomme C, Duluc I, Martin E, et al. The Cdx2 homeobox gene has a tumour suppressor function in the distal colon in addition to a homeotic role during gut development. Cuf. 2003;52:1465-1471.

16. Aoki K, Tamai Y, Horiike S, Oshima M, Taketo MM. Colonie polyposis caused by mTOR-mediated chromosomal instability in Apc+/ Delta71 6 Cdx2 compound mutant mice. Nat Genet. 2003;35:323-330.

17. MaIIo GV, Soubeyran P, Lissitzky JC, et al. Expression of the Cdx1 and Cdx2 homeotic genes leads to reduced malignancy in colon cancer-derived cells. 1 Biol Chem. 1998;273:14030-14036.

18. Yagi OK, Akiyama Y, Yuasa Y. Genomic structure and alterations of homeobox gene CDX2 in colorectal carcinomas. Br J Cancer. 1999;79:440-444.

19. Sivagnanasundaram S, Islam I, Talbot I, Drummond F, Walters JR, Edwards YH. The homeobox gene CDX2 in colorectal carcinoma: a genetic analysis. Br J Cancer. 2001 ;84:21 8-225.

20. Woodford-Richens KL, Halford S, Rowan A, et al. CDX2 mutations do not account for juvenile polyposis or Peutz-Jeghers syndrome and occur infrequently in sporadic colorectal cancers. Br J Cancer. 2001;84:1314-131 6.

21. Hinoi T, Loda M, Fearon ER. Silencing of CDX2 expression in colon cancer via a dominant repression pathway. J Biol Chem. 2003;278:44608-44616.

22. Wicking C, Simms LA, Evans T, et al. CDX2, a human homologue of Drosophila caudal, is mutated in both alleles in a replication error positive colorectal cancer. Oncogene. 1998;1 7:657-659.

23. Hinoi T, Tani M, Lucas PC, et al. Loss of CDX2 expression and microsatellite instability are prominent features of large cell minimally differentiated carcinomas of the colon. Am J Pathol. 2001;159:2239-2248.

24. Ee HC, Erler T, Bhathal PS, Young GP, James RJ. Cdx-2 homeodomain protein expression in human and rat colorectal adenoma and carcinoma. Am J Pathol. 1995)147:586-592.

25. Kaimaktchiev V, Terracciano L, Tornillo L, et al. The homeobox intestinal differentiation factor CDX2 is selectively expressed in gastrointestinal adenocarcinomas. Mod Pathol. 2004; 17:1392-1399.

26. Moskaluk CA, Zhang H, Powell SM, Cerilli LA, Hampton CM, Frierson HF Jr. Cdx2 protein expression in normal and malignant human tissues: an immunohistochemical survey using tissue microarrays. Mod Pathol. 2003;1 6:913-919.

27. Werling RW, Yaziji H, Bacchi CE, Gown AM. CDX2, a highly sensitive and specific marker of adenocarcinomas of intestinal origin: an immunohistochemical survey of 476 primary and metastatic carcinomas. Am J Surg Pathol. 2003;27: 303-310.

28. Barbareschi M, Murer B, Colby TV, et al. CDX-2 homeobox gene expression is a reliable marker of colorectal adenocarcinoma metastases to the lungs [see comment]. Am J Surg Pathol. 2003;27:141- 149.

29. Hamilton SR, Vogelstein B, Kudo S, et al. Carcinoma of the colon and rectum. In: Hamilton SR, Aaltonen LA, eds. Pathology and Genetics of Tumours of the Digestive System. Lyon, France: IARC Press; 2000:105-119. World Health Organization Classification of Tumours; vol 2.

30. Macdonald PM, Struhl G. A molecular gradient in early Drosophila embryos and its role in specifying the body pattern. Nature. 1986;324:537-545.

31. Duprey P, Chowdhury K, Dressier GR, et al. A mouse gene homologous to the Drosophila gene caudal is expressed in epithelial cells from the embryonic intestine. Genes Dev. 1988;2:1 647-1654.

32. James R, Kazenwadel J. Homeobox gene expression in the intestinal epithelium of adult mice. J Biol Chem. 1991;266:3246- 3251.

33. Gamer LW, Wright CV. Murine Cdx-4 bears striking similarities to the Drosophila caudal gene in its homeodomain sequence and early expression pattern. Mech Dev. 1993;43:71-81.

34. Freund JN, Domon-Dell C, Kedinger M, Duluc I. The Cdx-1 and Cdx-2 homeobox genes in the intestine. Biochem Cell Biol. 1998;76:957-969.

35. Almeida R, Suva E, Santos-Silva F, et al. Expression of intestine-specific transcription factors, CDX1 and CDX2, in intestinal metaplasia and gastric carcinomas. I Pathol. 2003:199:36- 40.

36. Croisman GM, Amar M, Meir A. Expression of the intestinal marker Cdx2 in the columnar-lined esophagus with and without intestinal (Barren's) metaplasia. Mod Pathol. 2004;1 7:1282-1288.

37. Phillips RW, Frierson HF Jr, Moskaluk CA. Cdx2 as a marker of epithelial intestinal differentiation in the esophagus. Am] Surg Pathol. 2003;27:1442-1447.

38. Adsay NV, Merati K, Basturk O, et al. Pathologically and biologically distinct types of epithelium in intraductal papillary mucinous neoplasms: delineation of an "intestinal" pathway of carcinogenesis in the pancreas. Am J Surg Pathol. 2004;28:839-848.

39. Cathro HP, Mills SE. lmmunophenotypic differences between intestinaltype and low-grade papillary sinonasal adenocarcinomas: an immunohistochemical study of 22 cases utilizing CDX2 and MUC2. Am 1 Surg Pathol. 2004;28: 1026-1032.

40. Mazziotta RM, Borczuk AC, Powell CA, Mansukhani M. CDX2 immunostaining as a gastrointestinal marker: expression in lung carcinomas is a potential pitfall. Appl lmmunohistochem MoI Morphol. 2005;13:55-60.

41. Rossi G, Murer B, Cavazza A, et al. Primary mudnous (so- called colloid) carcinomas of the lung: a clinicopathologic and immunohistochemical study with special reference to CDX-2 homeobox gene and MUC2 expression. Am J Surg Pathol. 2004;28:442-452.

42. Wu XS, Akiyama Y, lgari T, et al. Expression of homeodomain protein CDX2 in gallbladder carcinomas. I Cancer Res Clin Oncol. 2005;131:271-278.

43. Logani S, Oliva E, Arnell PM, Amin MB, Young RH. Use of novel immunohistochemical markers expressed in colonie adenocarcinoma to distinguish primary ovarian tumors from metastatic colorectal carcinoma. Mod Pathol. 2005; 18:19-25.

44. Barbareschi M, Roldo C, Zamboni G, et al. CDX-2 homeobox gene product expression in neuroendocrine tumors: its role as a marker of intestinal neuroendocrine tumors. Am I Surg Pathol. 2004;28:1169-11 76.

45. Saqi A, Alexis D, Remotti F, Bhagat G. Usefulness of CDX2 and TTF-1 in differentiating gastrointestinal from pulmonary carcinoids. Am] Clin Pathol. 2005; 123:394-404.

46. Erickson LA, Papouchado B, Dimashkieh H, Zhang S, Nakamura N, Lloyd RV. Cdx2 as a marker for neuroendocrine tumors of unknown primary sites. Fncfocr Pathol. 2004;! 5:247-252.

Lindsey B. De Lott, BS; Carl Morrison, MD, DVM; Saul Suster, MD; David E. Cohn, MD; Wendy L. Frankel, MD

Accepted for publication May 16, 2005.

From the Departments of Pathology (Ms De Lott and Drs Morrison, Suster, and Frankel) and Obstetrics and Gynecology (Dr Cohn), The Ohio State University Medical Center, Columbus.

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Wendy L. Frankel, MD, Department of Pathology, The Ohio State University, E-401 Doan Hall, 410 W Tenth Ave, Columbus, OH 43210-1228 (e-mail: frankel-1@medctr.osu.edu).

Copyright College of American Pathologists Sep 2005

Source: Archives of Pathology & Laboratory Medicine

More News in this Category